Gene arrays and temporal patterns of drug response: corticosteroid effects on rat liver.

It was hypothesized that expression profiling using gene arrays can be used to distinguish temporal patterns of changes in gene expression in response to a drug in vivo, and that these patterns can be used to identify groups of genes regulated by common mechanisms. A corticosteroid, methylprednisolone (MPL), was administered intravenously to a group of 47 rats ( Rattus rattus) that were sacrificed at 17 timepoints over 72 h after MPL administration. Plasma drug concentrations and hepatic glucocorticoid receptors were measured from each animal.

Relative immunosuppressive potency of therapeutic corticosteroids measured by whole blood lymphocyte proliferation.

The in vitro immunosuppressive potency of several therapeutic corticosteroids was investigated using a whole-blood lymphocyte proliferation assay. The selected steroids included beclomethasone dipropionate (BDP), betamethasone (BET), budesonide (BUD), dexamethasone (DEX), flunisolide (FLU), fluticasone propionate (FTP), hydrocortisone (HC), methylprednisolone (MPL), prednisolone (PNL), and triamcinolone acetonide (TAA). The ability of phytohemagglutinin to stimulate lymphocytes in whole blood samples obtained from six drug-free male volunteers was tested against drug concentrations ranging from approximately 0.

Modeling of corticosteroid pharmacogenomics in rat liver using gene microarrays.

Corticosteroid (CS) pharmacogenomics was studied using gene microarrays in rat liver. Methylprednisolone (MPL) was administered intravenously at 50 mg/kg. Rats were sacrificed and liver excised at 17 time points over 72 h.

Comparative pharmacokinetics of coumarin anticoagulants L: Physiologic modeling of S-warfarin in rats and pharmacologic target-mediated warfarin disposition in man.

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.

Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia.

Purpose: To evaluate the plasma protein binding and pharmacokinetics of prednisolone during therapeutic use in children with acute lymphoblastic leukemia (ALL) using the population approach.

Methods: A two-compartment pharmacokinetic model was used to describe data from 23 children with ALL (aged 2-15 years). Prednisolone (60 mg/m(2) per day in three divided doses) was administered both orally and intravenously, and samples were obtained on several days during the initial 5 weeks of remission induction therapy.

Diversity of mechanism-based pharmacodynamic models.

Pharmacodynamics is the study of the time course of pharmacological effects of drugs. The field of pharmacodynamic modeling has made many advances, due in part to the relatively recent development of basic and extended mechanism-based models. The purpose of this article is to describe the classic as well as contemporary approaches, with an emphasis on pertinent equations and salient model features.

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys.

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c.

Integrated QSPR--pharmacodynamic model of genomic effects of several corticosteroids.

The results from a quantitative structure-property relationship (QSPR) model was integrated into a fifth-generation pharmacokinetic/pharmacodynamic (PK/PD) model of corticosteroid receptor/gene-mediated effects. The proposed model was developed using previously reported tyrosine aminotransferase (TAT) activity data following a 50 mg/kg intravenous dose of methylprednisolone in male adrenalectomized (ADX) rats. Induced TAT activity is a classical measure of corticosteroid genomic effects and the typical time course shows an initial lag-time, a slow rise to peak response, and a gradual return toward baseline values.

Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole.

Background: Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival.

Methods: Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]).

Results: Prednisolone area under the curve (AUC)-dose-normalized (PNAUCn) to 1 mg/kg was 8,288+/-1,513 ng.

Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys.

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize interferon after i.v. and s.

Multiple-pool cell lifespan model of hematologic effects of anticancer agents.

The leukopenic effects of anticancer agents are described using a semi-physiologic multiple-pool cell lifespan model. The time course of myelosuppression in relation to the drug concentration vs. time profile was characterized using a three pool indirect model.

Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in humans.

Purpose: An integrated receptor-based pharmacokinetic/pharmacodynamic (PK/PD) model of interferon-beta la (IFN-beta la) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans.

Methods: Data were extracted from the literature by digitalization. Single-dose (3 IV doses and I SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program.

Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers.

Objectives: The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers.

Methods: An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8.

Quantitative structure-pharmacokinetic/pharmacodynamic relationships of corticosteroids in man.

The purpose of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for 11 selected corticosteroids in man. Multiple linear regression analysis with an automatic forward step-wise inclusion algorithm was used to construct QSAR/QSPKR models from molecular and submolecular descriptors that were generated using the SYBYL and KowWin computer programs. The final equations describing steroid relative receptor affinity, systemic clearance, volume of distribution, fraction unbound in plasma, and percent of oral absorption, all showed significant correlations (R(2) range 0.

Pharmacodynamics and pharmacogenomics of diverse receptor-mediated effects of methylprednisolone in rats using microarray analysis.

Corticosteroids such as methylprednisolone (MPL) produce many of their anti-inflammatory, immunosuppressive, and exaggerated physiological effects by receptor and gene-mediated mechanisms. The temporal pattern of change in four genes in rat tissues was measured by quantitative Northern hybridization and rtPCR after a single dose of MPL. Two profiles were observed: two genes with enhanced expression showed a slow onset and moderate rate of decline within a 24 hr time frame while two genes with reduced expression exhibited a rapid onset and prolonged suppression over a > or = 72 hr time span.

Fifth-generation model for corticosteroid pharmacodynamics: application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats.

A fifth-generation model for receptor/gene-mediated corticosteroid effects was proposed based on results from a 50 mg/kg i.v. bolus dose of methylprednisolone (MPL) in male adrenalectomized rats, and confirmed using data from other acute dosage regimens.

Pharmacodynamic modeling of thrombopoietin, platelet, and megakaryocyte dynamics in patients with acute myeloid leukemia undergoing dose intensive chemotherapy.

A proposed model of thrombopoietin (TPO) regulation is that of a constitutive production of TPO with circulating levels being predominately regulated by changes in platelet and megackaryocyte mass. Using a pharmacodynamic (PD) approach, the authors examined the validity of this model for patients with acute myeloid leukemia (AML) undergoing dose-intensive postinduction chemotherapy (HDT). TPO and platelet values were assayed weekly in AML patients undergoing HDT.

General pharmacokinetic model for drugs exhibiting target-mediated drug disposition.

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents.

Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation.

Aims: Mitogen-induced ex vivo whole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three-component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression.

Methods: An oral dose (0.

Pharmacodynamic interaction of recombinant human interleukin-10 and prednisolone using in vitro whole blood lymphocyte proliferation.

Prednisolone, a commonly used synthetic corticosteroid, and IL-10, a cytokine under investigation for strong antiinflammatory properties, are being contemplated as a potential joint therapeutic regimen in immune disorders. Their pharmacodynamic interactions were examined in blood from healthy adult male and female volunteers using an in vitro phytohemagglutinin (PHA)-stimulated whole-blood lymphocyte proliferation technique. Isobolograms along with parametric competitive and noncompetitive interaction models were used to determine the nature and intensity of interactions.

Pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) in cynomolgus monkeys after single oral and intravenous doses.

The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.

Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans.

Background: SB 249417 is a humanized anti-factor IX/IXa antibody that, on administration to rats and monkeys, produces an immediate suppression of factor IX activity and prolongation of activated partial thromboplastin times (aPTT).

Objective: Our objective was to establish the pharmacokinetics of SB 249417 and to explore its effects on factor IX activity levels and aPTT in humans.

Methods: In this phase I, single-blind, randomized, placebo-controlled, parallel-group, single intravenous infusion study, individual and mean data from a total of 26 healthy volunteers at 5 dosing levels were analyzed.

Pharmacodynamics and pharmacogenomics of methylprednisolone during 7-day infusions in rats.

An array of adverse steroid effects was examined on a whole body, tissue, and molecular level. Groups of male adrenalectomized Wistar rats were subcutaneously implanted with Alzet mini-pumps giving zero-order release rates of 0, 0.1, and 0.

Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women.

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.

Prednisolone pharmacokinetics and pharmacodynamics in relation to sex and race.

Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase.